To Establish the Safety and Effectiveness of the ALPFA GRAIL PFA System for Treating Symptomatic Benign Prostate Hyperplasia (BPH) Also Known as an Enlarged Prostate.

A Prospective Randomized Pivotal Trial of the ALPFA Medical Prostate Ablation System Compared With Cystoscopy in Men With Symptomatic Benign Prostatic Hyperplasia

The main goal of this study is to evaluate the ALPFA GRAIL™ Pulsed Field Ablation (PFA) System for treatment of enlarged prostate (BPH) symptoms. The study will involve up to 250 male participants who have urinary problems caused by BPH and whom are greater than 40 years of age in up to 30 investigational centers across the US,Canada and European Union.

This study aims to test how safe and effective the ALPFA BPH PFA System is for treating men over age 40 who have urinary problems caused by an enlarged prostate (BPH).The study will involve up to 250 participants in up to 30 investigational centers across the US, Canada, and European Union.

Men who agree to join the study will have health checks before treatment. Those who meet the study eligibility criteria including medication washout requirements,will be placed by chance into one of two groups. Two out of three men will receive treatment with the ALPFA BPH PFA System. One out of three men will receive a sham procedure that looks like treatment but does not deliver treatment.Participants will be followed for longer term safety and effectiveness for a total of 5 years post treatment with the ALPFA GRAIL™ Pulsed Field Ablation (PFA) System.

Patients and site personnel administering follow-up assessments will be blinded to the randomized treatment through completion of the 3-month follow-up visit.

After 3 months, participants will be told which group they were in. Men who were in the sham group may choose to receive treatment with the ALPFA BPH PFA System. Men in the sham group who do not choose treatment by 6 months will no longer take part in the study.

All men who receive treatment will have follow-up visits at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months. After that, they will be checked once a year for up to 5 years.

Inclusion Criteria: Study subjects are required to meet all the following inclusion criteria to participate in this study as determined by the Investigator:

1. ≥ 45 years of age on the day of enrollment.

2. Symptomatic BPH meeting all of the following criteria determined within 30 days preceding enrollment and after fulfilling the concomitant medication washout period(s):

   1. Symptom Score: Baseline IPSS score ≥13
   2. Flow Rate: Single uroflow test with a minimum voided volume ≥ 125 mL and a Qmax ≥ 5 mL/sec and ≤ 12 mL/s
   3. Residual: ultrasound-determined PVR of ≤ 250 mL

3. Prostate size 25-150 g, measured by transrectal ultrasound.

4. Willing and able to provide consent and comply with study requirements.

Exclusion Criteria:Subjects will be excluded from the study if they meet any one of the following exclusion criteria, as determined by the Investigator:

1. Medical conditions that would prevent participation in the study, interfere with assessment or therapy, significantly raise the risk of study participation, or confound data or its interpretation, including but not limited to:

   1. Cardiovascular:

      • History of clinically significant heart failure (NYHA III/IV)
      • Uncontrolled arrhythmia.
      • Stroke, TIA, myocardial infarction, unstable angina, percutaneous coronary intervention, or any cardiac surgery within 180 days of enrollment.
      • Uncontrolled hypertension

   2. Renal: Serum creatinine > 2.0 mg/dL or any history of renal dialysis or renal transplant.

   3. Metabolic: Clinically uncontrolled diabetes mellitus or a baseline HbA1c ≥ 8.0%, or clinically significant liver disease.

   4. Non-urologic cancer: Active malignancy, or within 3 years of enrollment, a history of treated malignancy now in full remission, except basal cell or squamous cell carcinoma of the skin.

   5. Respiratory: Severe lung disease or respiratory illness requiring hospitalization.

   6. Immunosuppression: Known immunosuppression, including but not limited to AIDS, immunosuppressive medication, or current chemotherapy.

   7. Transplant: Solid organ or hematologic transplant or currently being evaluated for an organ transplant.

   8. Substance abuse: Active alcoholism or drug addiction.

2. Urologic conditions that would prevent participation in the study, interfere with assessment or therapy, significantly raise the risk of study participation, or confound data or its interpretation, including but not limited to:

   1. Operative: Previous prostate surgery or interventional procedure, including but not limited to BPH surgery, radiation, laser, prostate arterial embolism, balloon dilatation, or hyperthermic treatment, or prostate biopsy within 40 days of the Index Procedure.
   2. Infection: Active urinary tract infection at the time of the Index Procedure (may be treated and enrolled upon negative urine culture).
   3. Incontinence: History of urinary incontinence.
   4. Retention: Requires indwelling catheter or intermittent catheterization to void or had an episode of spontaneous urinary retention within 30 days of enrollment.
   5. Prostatitis: History of prostatitis within 2 years of enrollment.
   6. Cystolithiasis: Active bladder stones
   7. Neurogenic bladder: Neurogenic or atonic bladder or sphincter, including etiologies of uncontrolled diabetes, Parkinson's disease, multiple sclerosis, cerebrovascular accident, or polyneuropathy.
   8. Anatomic abnormality: Prior or current urethral stricture, meatal stenosis, bladder neck contracture, or other urologic anatomic abnormalities that would interfere with planned treatment or confound subsequent assessment.
   9. Implants: Any urinary tract implants including stents, sutures, penile implants, or artificial sphincters.
   10. Hematuria: Hematuria without a known contributing factor within 90 days of the Index Procedure.

3. Bladder cancer: Actively being treated or suspected cancer of the bladder.

4. Baseline PSA > 10 ng/mL or confirmed or suspected prostate cancer (Subjects with a PSA level above 2.5 ng/mL, or age specific, or local reference ranges should have prostate cancer excluded to the Investigator's satisfaction following the site's standard of care.

5. Prior pelvic or rectal interventions:

   1. Previous pelvic irradiation or radical pelvic surgery
   2. Previous rectal surgery (other than hemorrhoidectomy) or a history of rectal disease that may be impacted by Index Procedure.

6. Peri-procedural anticoagulation: Unable to stop anti-platelet or anticoagulation treatment for the Index Procedure per site standard of care.

7. Subjects who cannot or will not comply with the following washout medication requirements within the time period specified prior to enrollment:

   1. 24-Hours:

      • i. Taking phenylephrine or pseudoephedrine within 24 hours of the Baseline evaluation and Index Procedure.

   2. 1 Week:

      • i. Antihistamine, anticonvulsant, or antispasmodics medications within 1 week of enrollment unless documented on a stable (unchanged) for 180 days prior to enrollment.

   3. 2 Weeks:

      • i. Use of alpha blockers or daily dosage of PDE5 inhibitors (tadalafil [Cialis]) for BPH within 2 weeks prior to enrollment.
      • ii. Use of anticholinergics or beta-3 adrenergic receptor agonists (e.g., mirabegron, vibegron) within 2 weeks prior to enrollment, unless documented on a stable dose for 30 days prior to enrollment.

   4. 3 Months:

      • i. Taking estrogen, drugs producing androgen suppression, or androgens within 90 days prior to enrollment, unless documented on a stable dosage for at least 90 days prior to enrollment.
      • ii. Use of Type II 5-alpha reductase inhibitor medication (e.g., finasteride [Proscar, Propecia]) within 90 days of enrollment OR anticipated use within the first 12 months of follow-up.

   5. 6 Months:

      • i. Use of any Type I 5-alpha reductase inhibitor medication (e.g., dutasteride [Avodart]) within 180 days prior to enrollment OR anticipate use within the first 12 months of follow-up.
      • ii. Taking tricyclic antidepressants that are not on a stable dose for the 180 days prior to enrollment OR anticipate stopping or changing treatment in the first 12 months of follow-up.

8. Subjects who wish to maintain their fertility.

9. Current or anticipated enrollment in any other randomized or interventional clinical study (registry or retrospective studies permitted).

10. Vulnerable populations, including individuals who are incarcerated or institutionalized.Any physical, psychological, or developmental impairment (e.g., developmental delay) that, in the investigator's opinion, would compromise the subject's ability to provide informed consent, comply with study procedures, or complete patient-reported outcome measures.